Ischemia-reperfusion induced microvascular responses in LDL-receptor -/- mice

The objective of this study was to determine whether the microvascular resp onses to ischemia and reperfusion (I/R) are altered in an animal model of a therosclerosis, the low-density lipoprotein-receptor knockout (LDLr -/-) mo use. Intravital video microscopy was used to monitor venular wall shear rat e, leukocytes rolling velocity, the number of rolling, adherent and emigrat ed leukocytes, and albumin leakage in cremasteric postcapillary venules of wild-type (B6129) and LDLr -/- mice exposed to 60 min of ischemia and 60 mi n of reperfusion. The postcapillary venules of LDLr -/- mice exhibited two- to threefold larger increments in the number of adherent leukocytes and a more profound albumin leakage response to I/R than venules in wild-type mic e. The exaggerated inflammatory responses noted in LDLr -/- mice placed on a normal diet were not exacerbated by a high-cholesterol diet. Treatment of LDLr -/- mice with either a platelet-activating factor (PAF) receptor anta gonist (WEB-2086) or a monoclonal antibody (YN-1) against the endothelial c ell adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), markedly attenuated the I/R-induced leukocyte adherence and albumin leakage. These findings indicate that atherogenic mice are more vulnerable to the deleteri ous microvascular effects of I/R and that PAF-mediated, ICAM-1-dependent le ukocyte adhesion contributes to this exaggerated response to I/R.